We studied three antimalarial treatments in Caala and Kuito, Angola, in 2002 and 2003. We tested chloroquine (CQ), amodiaquine (AQ) and sulfadoxine-pyrimethamine (SP) in Caala, and AQ, SP and the combinations AQ+artesunate (AQ+AS) and SP+artesunate (SP+AS) in Kuito. A total of 619 children (240 in Caala, 379 in Kuito) with uncomplicated Plasmodium falciparum malaria were followed-up for 28 days, with PCR genotyping to distinguish recrudescence from reinfection. PCR-corrected failure proportions at day 28 were very high in the CQ group (83.5%, 95% CI 74.1-90.5), high in the SP groups (Caala: 25.3%, 95% CI 16.7-35.8; Kuito: 38.8%, 95% CI 28.4-50.0), around 20% in the AQ groups (Caala: 17.3%, 95% CI 10.0-27.2; Kuito: 21.6%, 95% CI 14.3-30.6) and very low in the artemisinin-based combination groups (1.2%, 95% CI 0.0-6.4 for each combination AQ+AS and SP+AS). These results show that CQ and SP are no longer efficacious in Caala and Kuito and that the moderate efficacy of AQ is likely to be compromised in the short term if used as monotherapy. We recommend the use of AQ with AS, though this combination might not have a long useful therapeutic life because of AQ resistance.

We report below an in vivo antimalarial efficacy study conducted in 2002 in Bundi Bugyo, a district of western Uganda housing a large displaced population. We tested sulfadoxine-pyrimethamine (SP), amodiaquine (AQ) and the combination chloroquine plus SP (CQ + SP). A total of 268 children with uncomplicated Plasmodium falciparum malaria were followed-up for 28 days according to WHO recommendations, with PCR genotyping to distinguish late recrudescences from re-infections. PCR-adjusted failure proportions at day 28 were 37.0% (34/92, 95% CI 27.1-47.7) in the SP group, 20.6% (14/68, 95% CI 11.7-32.1) in the AQ group and 22.8% (18/79, 95% CI 14.1-33.6) in the CQ + SP group. Early failures were particularly frequent in the SP group (15.2%). Clearance of gametocytes was slower in the SP and CQ + SP groups than in the AQ group. This study suggests that, in Bundi Bugyo, CQ + SP (Uganda's first-line regimen) will need to be replaced by a more efficacious regimen. Across Uganda, the deployment of SP containing combinations may not be a feasible long-term strategy. For Bundi Bugyo, we recommend a combination of artesunate and AQ. Our study also confirms previous findings that resistance is considerably underestimated by 14-day follow-ups. Antimalarial policy decisions should therefore be based on 28-day studies, with PCR adjustment to distinguish re-infections.

The current first-line and second-line drugs for Plasmodium falciparum malaria in South Sudan, chloroquine and sulfadoxine-pyrimethamine (SP), were evaluated and compared with amodiaquine, in an MSF-Holland-run clinic in eastern Upper Nile, South Sudan from June to December 2001. Patients with uncomplicated malaria and fever were stratified by age group and randomly allocated to one of 3 treatment regimes. A total of 342 patients was admitted and followed for 14 d after treatment. The dropout rate was 10.2%. Of those who completed the study, 104 were treated with chloroquine (25 mg/kg, 3 d), 102 with SP (25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine, single dose) and 101 with amodiaquine (25 mg/kg, 3 d). Adequate clinical response was observed in 88.5% of patients treated with chloroquine, 100% of patients treated with SP and 94.1% of patients treated with amodiaquine. In children aged < 5 years, the success rate was lower: 83.3% for chloroquine and 93.0% for amodiaquine. In adults no treatment failures were found, but children aged 5-15 years showed intermediate levels. In addition, we determined the initial genotypes of dhfr and dhps of 44 isolates from the SP-treated group and > 80% were found to be wild type for dhfr and 100% for dhps. Two percent of isolates had a single mutation and 16% had double mutations of dhfr. These data are in full agreement with the clinical effectiveness of SP. A change in malaria treatment protocols for South Sudan is recommended.

Multi-drug resistant falciparum malaria is widespread in Asia. In Thailand, Cambodia and Vietnam the national protocols have changed largely to artesunate combined treatment regimens but elsewhere in East and South Asia chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) are still widely recommended by national malaria control programmes. In Kachin State, northern Myanmar, an area of low seasonal malaria transmission, the efficacy of CQ (25 mg base/kg) and SP (1.25/25 mg/kg), the nationally recommended treatments at the time, were compared with mefloquine alone (M; 15 mg base/kg) and mefloquine combined with artesunate (MA; 15:4 mg/kg). An open randomized controlled trial enrolled 316 patients with uncomplicated Plasmodium falciparum malaria, stratified prospectively into three age-groups. Early treatment failures (ETF) occurred in 41% (32/78) of CQ treated patients and in 24% of patients treated with SP (18/75). In young children the ETF rates were 87% after CQ and 35% after SP. Four children (two CQ, two SP) developed symptoms of cerebral malaria within 3 days after treatment. By day 42, failure rates (uncorrected for reinfections) had increased to 79% for CQ and 81% for SP. ETF rates were 2.5% after treatment with M and 3.9% after treatment with MA (P > 0.2). Overall uncorrected treatment failure rates at day 42 following M and MA were 23% and 21%, respectively. Chloroquine and SP are completely ineffective for the treatment of falciparum malaria in northern Myanmar. Mefloquine treatment is much more effective, but three day combination regimens with artesunate will be needed for optimum efficacy and protection against resistance.

OBJECTIVE: To assess the efficacy of antimalarial treatment and molecular markers of Plasmodium falciparum resistance in the Chittagong Hill Tracts of Bangladesh. METHODS: A total of 203 patients infected with P. falciparum were treated with quinine 3 days plus sulphadoxine/pyrimethamine (SP) combination therapy, and followed up during a 4-week period. Blood samples collected before treatment were genotyped for parasite mutations related to chloroquine (pfcrt and pfmdr1 genes) or SP resistance (dhfr and dhps). RESULTS: Of 186 patients who completed follow-up, 32 patients (17.2%) failed to clear parasitaemia or became positive again within 28 days after treatment. Recurring parasitaemia was related to age (chi(2) = 4.8, P < 0.05) and parasite rates on admission (t = 3.1, P < 0.01). PCR analysis showed that some of these cases were novel infections. The adjusted recrudescence rate was 12.9% (95% CI 8.1-17.7) overall, and 16.6% (95% CI 3.5-29.7), 15.5% (95% CI 8.3-22.7) and 6.9% (95% CI 0.4-13.4) in three age groups (<5 years, 5-14, > or =15). The majority of infections carried mutations associated with chloroquine resistance: 94% at pfcrt and 70% at pfmdr. Sp-resistant genotypes were also frequent: 99% and 73% of parasites carried two or more mutations at dhfr and dhps, respectively. The frequency of alleles at dhfr, dhps and pfmdr was similar in cases that were successfully treated and those that recrudesced. CONCLUSIONS: The clinical trial showed that quinine 3-days combined to SP is still relatively effective in the Chittagong Hill Tracts. However, if this regimen is continued to be widely used, further development of SP resistance and reduced quinine sensitivity are to be expected. The genotyping results suggest that neither chloroquine nor SP can be considered a reliable treatment for P. falciparum malaria any longer in this area of Bangladesh.

Falciparum Malaria is hyperendemic in southern Nigeria and chloroquine resistance is an increasing problem. Therefore, the parasitological and haematological response to treatment with amodiaquine was studied in children under 5 years during a 14-day follow-up. Of 105 children who accomplished the study (out of 114 who were enrolled), 95.3% were parasite-negative on thick blood film on day 7, which decreased to 89.5% on day 14. The haemoglobin levels increased on average by 1.3% on day 14 (+/-1.9) and more pronounced in children with anaemia<10 g/dl on enrollment. The number of patients with adverse events (mainly pruritus and nausea) was few. This study shows that amodiaquine is effective, safe and affordable in an area with high resistance to chloroquine.

Bangladesh faces growing levels of Plasmodium falciparum resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP). Alternative antimalarial therapies, particularly combination regimens, need to be considered. Therefore, the efficacy of three antimalarial combination therapies was assessed in Chittagong Hill Tracts. A total of 364 P. falciparum patients were recruited and randomly assigned to either CQ + SP, mefloquine + artesunate (MQ + AS) or lumefantrine + artemether (Coartem). Results showed that CQ + SP therapy was less effective than the two artemisinin-based combination therapies. The day 42 PCR-corrected efficacy rate was 62.4% for CQ + SP, 100% for MQ + AS and 97.1% for Coartem. Failures occurred at a shorter interval after CQ + SP treatment than after Coartem. The artemisinin-based therapies effectively prevented development of gametocytes, whereas CQ + SP did not. All three therapies were well tolerated, although reports of mild complaints during treatment appeared higher with MQ + AS. We conclude that CQ + SP is not a viable option for replacing CQ monotherapy as first-line P. falciparum treatment in this area of Bangladesh. A change to artemisinin-based combination therapy is recommended. Both Coartem and MQ + AS appear to be good options, effective in curing P. falciparum malaria and in preventing recrudescences following treatment.

We report the results of an in vivo antimalarial efficacy study with chloroquine (CQ) and sulfadoxine/pyrimethamine (SP) conducted between 2003 and 2004 in Koumantou, southern Mali. A total of 244 children were included in the study; 210 children were followed-up for 28 days according to WHO recommendations, with PCR genotyping to distinguish late recrudescence from re-infection. Global failure proportions at Day 14, without taking into account re-infections, were 44.2% (95% CI 34.9-53.5%) in the CQ group and 2.0% (95% CI 0.0-4.8%) in the SP group. PCR-adjusted failure proportions at Day 28 were even higher in the CQ group (90.5% (95/105), 95% CI 84.8-96.2%) and relatively low in the SP group (7.0% (7/100), 95% CI 1.9-12.1%). These results show that CQ is no longer efficacious in Koumantou. The use of SP in monotherapy is likely to compromise its efficacy. We recommend the use of artemisinin-based combination therapy as first-line treatment for uncomplicated Plasmodium falciparum malaria in Koumantou.

We report two 28-day in-vivo antimalarial efficacy studies carried out in the urban centres of Bongor and Koumra, southern Chad. We assess chloroquine (CQ), sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) to treat Plasmodium falciparum uncomplicated malaria. Methods and outcome classification complied with latest WHO guidelines. Out of the 301 and 318 children aged 6-59 months included in Bongor and Koumra, respectively, 246 (81.7%) and 257 (80.8%) were eligible for analysis. In Bongor and Koumra, the 28-day PCR-adjusted failure rates for CQ were 23.7% (95% CI 14.7-34.8%) and 32.9% (95% CI 22.1-45.1%), respectively, and those for SP were 16.3% (95% CI 9.4-25.5%) and 4.3% (95% CI 1.2-10.5%). AQ failure rates were 6.4% (95% CI 2.1-14.3%) and 2.2% (95% CI 0.3-7.6%). The current use of CQ in Bongor and Koumra is questionable, and a more efficacious treatment is needed. Considering the reduced efficacy of SP in Bongor, AQ seems to be the best option for the time being. Following WHO recommendations that prioritize the use of artemisinin-based combinations, artesunate plus amodiaquine could be a potential first-line treatment. Nevertheless, the efficacy of this combination should be evaluated and the change carefully prepared, implemented and monitored.

To provide advice on the rational use of antimalarial drugs, Médecins Sans Frontières conducted a randomized, an open label efficacy study in Kajo Keji, an area of high transmission of malaria in southern Sudan. The efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) were measured in a 28-day in vivo study, with results corrected by PCR genotyping. Of 2010 children screened, 115 children aged 6-59 months with uncomplicated Plasmodium falciparum malaria were randomized into each group to receive a supervised course of treatment. Of these, 114, 103 and 111 were analysed in the CQ, SP and AQ groups, respectively. The overall parasitological failure rates at day 28 were 93.9% [95% confidence interval (CI) 87.3-97.3] for CQ, 69.9% (95% CI 60.0-78.3) for SP, and 25.2% (95% CI 17.7-34.5) for AQ. These results provide important missing data on antimalarial drug efficacy in southern Sudan. They indicate that none of the drugs could be used in monotherapy and suggest that even in combination with artemisinin, cure rates might not be efficacious enough. We recommend a combination of artemether and lumefantrine as first-line treatment for uncomplicated P. falciparum malaria cases in Kajo Keji county.

BACKGROUND: Having reliable forecasts is critical now for producers, malaria-endemic countries and agencies in order to adapt production and procurement of the artemisinin-based combination treatments (ACTs), the new first-line treatments of malaria. There is no ideal method to quantify drug requirements for malaria. Morbidity data give uncertain estimations. This study uses drug consumption to provide elements to help estimate quantities and financial requirements of ACTs. METHODS: The consumption of chloroquine, sulphadoxine/pyrimethamine and quinine both through the private and public sector was assessed in five sub-Saharan Africa countries with different epidemiological patterns (Senegal, Rwanda, Tanzania, Malawi, Zimbabwe). From these data the number of adult treatments per capita was calculated and the volumes and financial implications derived for the whole of Africa. RESULTS: Identifying and obtaining data from the private sector was difficult. The quality of information on drug supply and distribution in countries must be improved. The number of adult treatments per capita and per year in the five countries ranged from 0.18 to 0.50. Current adult treatment prices for ACTs range US$ 1-1.8. Taking the upper range for both volumes and costs, the highest number of adult treatments consumed for Africa was estimated at 314.5 million, corresponding to an overall maximum annual need for financing ACT procurement of US$ 566.1 million. In reality, both the number of cases treated and the cost of treatment are likely to be lower (projections for the lowest consumption estimate with the least expensive ACT would require US $ 113 million per annum). There were substantial variations in the market share between public and private sources among these countries (the public sector share ranging from 98% in Rwanda to 33% in Tanzania). CONCLUSION: Additional studies are required to build a more robust methodology, and to assess current consumptions more accurately in order to better quantify volumes and finances for production and procurement of ACTs.

OBJECTIVES: To provide nationally relevant information on the antimalarial efficacy of chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) in Sierra Leone, with a view to updating antimalarial policy in the country. METHODS: Between October 2002 and May 2003, standard WHO methodology for in vivo efficacy assessment was used in five sites to study the therapeutic response of 6-59 months old uncomplicated Plasmodium falciparum malaria cases treated with CQ (n = 247), SP (n = 353) or AQ (n = 434). Follow-up was of 28 days, with polymerase chain reaction genotyping to distinguish late recrudescences from re-infections. RESULTS: Overall 85.3% of patients reached an analysable endpoint. CQ failure proportions were very high, ranging from 39.5% (95% CI: 25.0-55.6) in Kabala to 78.8% (65.3-88.9) in Kailahun. Early failures under CQ were frequent. SP efficacy was also disappointing, with failure from 23.2% (13.9-34.9) in Kabala to 46.1% (35.4-57.0) in Kailahun. AQ resistance was more moderate, ranging from 5.4% (1.8-12.1) in Makeni to 29.8% (20.3-40.8) in Kailahun, with almost no early failures. AQ also provided more rapid fever and parasite clearance. CONCLUSION: In a consensus meeting organized by the Ministry of Health and Sanitation, and based on these findings, artesunate (AS) + AQ and artemether-lumefantrine (Coartemtrade mark) were identified as the only options to rapidly replace CQ. The choice fell on AS + AQ because of expected high efficacy, lower cost in a blister presentation, and the absence of safety data on artemether-lumefantrine in pregnancy. Donor support is required to support this policy change. Throughout Africa, as SP resistance increases, these two regimens are probably the only options available while newer combinations are developed. Efficacy studies should focus on testing AQ and AS + AQ.

Both northern and southern Sudan are deploying artemisinin-based combinations against uncomplicated Plasmodium falciparum malaria (artesunate+sulfadoxine-pyrimethamine [AS+SP] in the north, artesunate+amodiaquine [AS+AQ] in the south). In 2003, we tested the efficacy of 3 day AS+SP and AS+AQ regimens in vivo in the isolated, seasonally endemic Nuba Mountains region (the first study of AS combinations in southern Sudan). We also analysed pre-treatment blood samples for mutations at the P. falciparum chloroquine transporter (Pfcrt) gene (associated with CQ resistance), and at the dihydrofolate reductase (Dhfr) gene (associated with pyrimethamine resistance). Among 161 randomized children under 5 years, PCR-corrected cure rates after 28 days were 91.2% (52/57, 95% CI 80.7-97.1) for AS+SP and 92.7% (51/55, 95% CI 82.4-98.0) for AS+AQ, with equally rapid parasite and fever clearance. The Pfcrt K76T mutation occurred in 90.0% (144/160) of infections, suggesting CQ would work poorly in this region. Overall, 82.5% (132/160) carried mutations at Dhfr (N51I, C59R or S108N, but not I164L), but triple mutants (more predictive of in vivo SP failure) were rare (3.1%). CQ use should be rapidly discontinued in this region. SP resistance may propagate rapidly, and AS+AQ is likely to be a better long-term option, provided AQ use is limited to the combination.

The objectives of these analyses were to assess the feasibility of the latest WHO recommendations (28-day follow-up with PCR genotyping) for the assessment of antimalarial drug efficacy in vivo and to examine how different statistical approaches affect results. We used individual-patient data from 13 studies of uncomplicated pediatric falciparum malaria conducted in sub-Saharan Africa, using chloroquine (CQ), sulfadoxine/pyrimethamine (SP), or amodiaquine (AQ). We assessed the use effectiveness and test performance of PCR genotyping in distinguishing recurrent infections. In analyzing data, we compared (i) the risk of failure on target days (days 14 and 28) by using Kaplan-Meier and per-protocol evaluable patient analyses, (ii) PCR-corrected results allowing (method 1) or excluding (method 2) new infections, (iii) and day 14 versus day 28 results. Of the 2,576 patients treated, 2,287 (89%) were evaluable on day 28. Of the 695 recurrences occurring post-day 14, 650 could be processed and 584 were resolved (PCR use effectiveness, 84%; test performance, 90%). The risks of failure on day 28 with Kaplan-Meier and evaluable-patient analyses tended to be generally close (except in smaller studies) because the numbers of dropouts were minimal, but attrition rates on day 28 were higher with the latter method. Method 2 yielded higher risks of failure than method 1. Extending observation to 28 days produced higher estimated risks of failure for SP and AQ but not for CQ (high failure rates by day 14). Results support the implementation of the current WHO protocol and favor analyzing PCR-corrected outcomes by Kaplan-Meier analysis (which allows for dropouts) and retaining new infections (which minimizes losses).

BACKGROUND: Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps) gene and mapped their contemporary distribution. METHODS AND FINDINGS: We used microsatellite polymorphism flanking the dhps gene to determine which resistance alleles shared common ancestry and found five major lineages each of which had a unique geographical distribution. The extent to which allelic lineages were shared among 20 African Plasmodium falciparum populations revealed five major geographical groupings. Resistance lineages were common to all sites within these regions. The most marked differentiation was between east and west African P. falciparum, in which resistance alleles were not only of different ancestry but also carried different resistance mutations. CONCLUSIONS: Resistant dhps has emerged independently in multiple sites in Africa during the past 10-20 years. Our data show the molecular basis of resistance differs between east and west Africa, which is likely to translate into differing antifolate sensitivity. We have also demonstrated that the dispersal patterns of resistance lineages give unique insights into recent parasite migration patterns.

In Rakhine State, on the western border of Myanmar, the efficacy of chloroquine (CQ) and pyrimethamine/ sulfadoxine (PS), the current treatments for uncomplicated Plasmodium falciparum malaria in this area, was evaluated in an open comparative study of 289 patients, stratified prospectively into 3 age groups. Chloroquine treatment was associated with more rapid clinical recovery (P = 0.03), but the overall cure rates were worse than for PS treatment; failure to clear parasitaemia or recrudescence within 14 d occurred in 72% (102/141) of cases treated with CQ compared to 47% (69/148) of those who received PS (P < 0.0001, adjusted for age). Failure rates at day 28 increased to 82% (116/141) in the CQ group and 67% (99/148) in the PS group (P = 0.003). The risk of treatment failure was significantly higher in children under 15 years old than in adults for both CQ (relative risk [RR] = 2.6; 95% confidence interval [95% CI] 1.3-5.2) and PS (RR = 2.2; 95% CI 1.4-3.3). Mefloquine (15 mg base/kg) proved to be highly effective as a treatment for CQ and PS resistant P. falciparum; only 2 of 75 patients (3%) had early treatment failures (< or = day 7), and the overall failure rate by day 42 was 7%. There is a very high level of chloroquine and PS resistance in P.falciparum on the western border of Myanmar, but mefloquine was effective in the area.

OBJECTIVE: To assess the efficacy of chloroquine in the treatment of Plasmodium vivax malaria in in Dawei District, southern Myanmar. METHODS: Enrolled patients at Sonsinphya clinic >6 months of age were assessed clinically and parasitologically every week for 28 days. To differentiate new infections from recrudescence, we genotyped pre- and post-treatment parasitaemia. Blood chloroquine was measured to confirm resistant strains. RESULTS: Between December 2002 and April 2003, 2661 patients were screened, of whom 252 were included and 235 analysed. Thirty-four per cent (95% CI: 28.1-40.6) of patients had recurrent parasitaemia and were considered treatment failures. 59.4% of these recurrences were with a different parasite strain. Two (0.8%) patients with recurrences on day 14 had chloroquine concentrations above the threshold of 100 ng/ml and were considered infected with chloroquine resistant parasites. 21% of failures occurred during the first 3 weeks of follow-up: early recurrence and median levels of blood chloroquine comparable to those of controls suggested P. vivax resistance. CONCLUSIONS: Plasmodium vivax resistance to chloroquine seems to be emerging in Dawei, near the Thai-Burmese border. While chloroquine remains the first-line drug for P. vivax infections in this area of Myanmar, regular monitoring is needed to detect further development of parasite resistance.

A four-arm drug sensitivity study compared chloroquine, sulfadoxine-pyrimethamine (SP), mefloquine and mefloquine-artesunate in Sonitpur and Karbi Anglong districts in Assam state, India. Two criteria were used to ascertain outcome: success of clinical treatment and parasitologic cure. In Sonitpur, at 14 days, there were 36/56 early and late treatment failures plus late parasitologic failures to chloroquine and 16/56 for SP. In Karbi Anglong, combined treatment failure at 14 days was 16/56 to chloroquine and 8/60 to SP. Mefloquine and mefloquine-artesunate demonstrated 93.9% and 93.6% sustained responses respectively at 42 days. High failure rates to both chloroquine and SP preclude the use of these drugs as first-line treatment for uncomplicated falciparum malaria in this region. A mefloquine-artesunate combination presents an effective alternative utilizing the currently recommended higher dose of mefloquine.

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